International patent application WO 2007/096393 A1 (Applicant: Nycomed) describes the preparation of racemic tetrahydro-β-carboline-hydantoines linked to a basic side chain by hydantoine-annulation of Pictet-Spengler β-carboline with (among others) haloethyl-isocyanate, with subsequent amination reaction of the haloethyl-sidechain. The halooethyl-isocyanates (Hal=Br, Cl, I) are applied as bifunctional reagents, to act both as building block in the heterocyclization step, leading to the hydantoine-moiety and as a linker to a broad range of different residues added to the tetrahydro-indolopyridine-core structure. This concept allows to effectively set up a compound library with broad diversity.
U.S. Pat. No. 6,143,757A (Applicant: ICOS Corp.) describes the preparation of cis- and trans-fused tetrahydro-1H-imidazo[1′,5″:1,6]pyrido[3,4-b]indole-1,3(2H)-dione analogues as a novel class of highly potent and selective PDE5 inhibitors. The heterocyclization to the hydantoine unit is achieved with carbonyldiimidazole-activation of primary amines, including N,N-dimethyl-ethane-1,2-diamine.
A. Daugan et al., J. Med. Chem., 2003, Vol. 46, 4525-32, also describes the procedure of U.S. Pat. No. 6,143,757A for reaction of trans-substituted racemic β-carbolines, obtaining the 2-(dimethylamino)ethyl-derivative in 64.5% after crystallization.
M. F. Brana et al., Lieb. Ann. Chemie, 1992, 867-869, describes a “one-pot synthesis of a 2-dialkylaminoalkyl-substituted tetrahydro-β-carboline-hydantoine system”, “as a new and convenient method for the synthesis of pharmacologically interesting compounds containing the tetrahydro-β-carboline-hydantoin moiety linked to a basic chain.” Various diamino substituted alkyl-spacers, including N,N-dimethyl-1,2-diamino-ethane were treated with carbonyldiimidazole prior to the annulation step. Annulation products were obtained in moderate yields (38-50%) as racemic mixtures.
Sunder-Plassmann et al., Bioorg. Med. Chem. 13 (22), 2005, 6094-6111 describes “Synthesis and Biological evaluation of new tetrahydro-β-carbolines as inhibitors of the mitotic kinesin Eg5”, starting from 1-(3-hydroxyphenyl)-carboline-3-carboxylic acids and various alkyl-isocyanate-building blocks.
None of the processes cited above appear to be suitable for the industrial large scale preparation of enantiomerically pure (stereomerically pure) tetracyclic tetrahydro-β-carboline-hydantoines linked to a basic chain with the required overall efficiency.
As described above, prior art processes for hetero-annulation reactions building up a hydantoine ring with a basic side chain, is only available for racemic β-carboline compounds missing the alkyl-substitution in 3-position (i.e. with reduced sterical hindrance at the β-carboline framework) and with insufficient chemical yield. The two-step approach with haloethyl-isocyanate-coupling followed by halogen-amine-substitution, described in WO2007/096393 needs the search for an alternative process due to the critical toxicity of haloethylisocyanates, namely bromo- or chloroethylisocyanate, together with the additional work-demand for the twostep procedure. Besides that, there are difficulties in driving the annulation reactions to sufficient yields above ca. 50%, not to forget additional problems during the amination step, which is hampered by the very low solubility of produced haloethyl-hydantoine plus safety and ecology issues running the process with low boiling dimethylamine in a pressurized reactor.